Inflammatory bowel disease (IBD) encompasses a spectrum of chronic, idiopathic inflammatory disorders of the gastrointestinal (GI) tract. Disease onset occurs most frequently in early adult life, thus requiring disease management over a lifetime. In the United States alone, over one million people have ulcerative colitis and Crohn's disease, the principal manifestations of IBD. Similar incidences of IBD-related disorders have been reported in the developed countries around the world.
Medical science has not yet discovered a cause or cure for IBD. Aminosalicylates (i.e., 5-aminosalicylic acid and azine compounds structurally related to it) continue to be the initial treatment of choice for both ulcerative colitis and Crohn's disease and are often prescribed to induce or maintain remission as IBD advances in severity. Multi-gram doses of 5-aminosalicylic acid (ASA) and related azine prodrugs, including sulfasalazine, azodisalicylate, and salicylazobenzoic acid, are, in fact, used daily by over half of IBD patients.
Aminosalicylates are topical anti-inflammatory agents. The limited data that are available suggest that the anti-inflammatory effects exhibited by ASA preparations are typical of those observed for phenols. In other words, ASA can act as a reducing agent for oxidants (such as hydroxyl radical, hypohalous acids, and peroxynitrite) and for peroxide intermediates such as the endoperoxides that are formed from arachidonic acid by the action of cyclooxygenase or lipoxygenase. Sandoval et at., for example, have recently reported that ASA is a potent scavenger of peroxynitrite and attenuated peroxynitrite-induced apoptosis in a human intestinal epithelial cell line. [A. Sandoval, et al., Gastroenterology 113, 1480–1488 (1997)] Likewise, ASA appears to be a potent scavenger of oxygen- and nitrogen-derived free radicals, which are produced in greater numbers in patients with IBD. (In contrast, N-acetyl-ASA, the principal metabolite of ASA, does not show this activity.) As a salicylate, ASA would be expected to be a metal chelator. Compelling evidence for a protective effect by metal chelation, however, has not been presented. In addition, a number of reports suggest inhibitory activities of ASA that are not related to its ability to undergo oxidation or chelate metals. For example, ASA can inhibit both cyclooxygenase and lipoxygenase, although its potency in this regard is low and apparently concentration dependent.
Despite widespread prescriptive use, neither ASA nor any of its current prodrug forms appears to be an effective treatment for disease of the distal ileum, one of the most common sites for initial IBD onset or relapse. Based on an understanding of the mechanisms of therapeutic action, a substantial basis for this relative lack of therapeutic benefit of oral ASA for patients with advancing IBD can be ascribed to the inability, using available drugs and delivery methods, to deliver therapeutically effective doses of ASA topically to the ileum and to the ileum and colon. Among the ASA drug delivery problems that have not been adequately addressed by current ASA drugs and dosage forms are:    Significant (25–95%) ASA absorption in the proximal ileum following oral administration.    Intracellular uptake and enzymatic conversion to N-acetyl-ASA, an inactive metabolite.    ASA transfer from the GI tract to the systemic circulation, where salicylates are known to inhibit platelet aggregation and exhibit kidney toxicity.
By way of illustration, most unmodified ASA dosage forms (i.e., suspensions, uncoated tablets or capsules containing uncoated ASA) apparently fail to deliver drug to the distal ileum and colon. For example, Yu et al. studied the pharmacological profile of an ASA oral suspension in healthy subjects who had fasted prior to dosage. [D. K. Yu, et al., J. Clin. Pharmacol 48, 273–277 (1995)] They found that following ingestion of 40 mL of a suspension of 1 g of ASA in water, there was rapid intestinal uptake of the drug. Within an hour post-dose, the maximum plasma concentrations of the drug and its N-acetylated metabolite N-acetyl-ASA (14.7 and 11.4 μg/mL, respectively) were observed. Within 12 hours the plasma concentrations of these salicylates had decreased to near baseline values. Moreover, less than 1% of the dose was isolated from feces. Since the primary sites of drug uptake are located in the proximal ileum, both observations suggest that little drug reached the distal ileum and colon, the disease sites for most CD patients.
Current techniques for targeting ASA to the ileum and colon comprise solid formulations of the drug molecules that are coated with a pH-sensitive polymeric coating. For example, enteric-release tablet dosage forms of ASA consist of drug particles that are coated with methyl or ethyl cellulose and/or tablets that are coated with a polymer that disintegrates and releases drug at pH 6 and higher. Enteric coating formulations are known which can be used to deliver drugs to the distal ileum, including shellac, acrylic acid derivatives, ethyl cellulose, and cellulose acetate phthalate. [Levine et al., Gastroenterology 92: 1037–1044 (1987)]
Drug delivery by enteric-release tablet dosage forms of ASA is better than that of uncoated ASA but continues to present several significant problems. For example, a number of reports confirm that a large and variable percentage of the drug is absorbed in the proximal ileum, decreasing by an unknown and potentially widely variable magnitude the concentration of ASA present at sites of inflammation. [See, for example, M. DeVos, et al., Gut 33, 1338–1342 (1992); L. A. Christensen, et al., Aliment. Pharmacol. Therap. 4, 523–533 (1990).] As a result of absorption, relatively high concentrations of ASA circulate systemically, potentially presenting salicylate-related safety issues for the patient (e.g., interference with platelet aggregation and kidney damage). A substantial percentage of the drug is converted enzymatically to N-acetyl-ASA, an inactive metabolite.
Azines are a class of ASA-prodrugs traditionally used in the treatment of IBD. Each azine comprises ASA linked to a second molecule by an azo (—N═N—) bond. The azine resists both chemical and enzymatic degradation in the small intestine. The covalently bound ASA that is incorporated in the azine is carried to the colon, where bacterial enzymes reduce the azo bond, thereby releasing the anti-inflammatory ASA at the target site. [U. Klotz, Clin. Pharmacokin. 10: 285 (1985)]
While an azine is useful for ASA-delivery to the colon, insufficient 5-aminosalicylic acid is released in the ileum to provide beneficial pharmacological action. Further, the second molecule that is linked to ASA generally has clinical side effects that are undesirable. For example, Khan has reported that the sulfapyridine moiety of the azine sulfasalazine is responsible for many of the undesirable side effects of the azine drug, including nausea, headache, rash, hemolytic anemia, decreased fertility and hepatic toxicity. [A. K. Azad Khan, et al., Lancet 2, 892–895 (1977)] In addition, it is reasonable to anticipate that the composition of colonic flora will differ from patient to patient, introducing a potentially variable ability to reduce the azo bond and release ASA in the colon. For these and other reasons, the azines do not address the need for ASA delivery to the distal ileum or the distal ileum and colon.
Several investigational approaches for ASA delivery have also been reported. A modified method to deliver ASA to the colon was reported by Brown, Parkinson, and co-workers who, in order to eliminate the effects of the sulfapyridine fraction, azo-linked sulfasalazine to a high molecular weight polymeric backbone. [J. P. Brown, et al., J. Med. Chem. 26: 1300 (1983)] The resulting water-soluble polymer was shown to release ASA in the presence of anaerobic rat cecal bacteria. Pharmacodynamic analysis showed that the polymer also decreased the carrageenan-induced, ulcerative colitis-like inflammatory response in guinea pigs, based on quantitative histopathological results. This pharmacodynamic response was found to be equal to the one achieved after direct administration of ASA and superior to sulfasalazine.
The covalent functionality of aza-aromatic compounds, susceptible to cleavage by the colonic bacteria, was also utilized by Saffran and co-workers. [M. Saffran, et al., J. Pharm. Sci. 77: 33 (1988)] It was postulated that a solid dosage form coated with copolymers of styrene and hydroxyethyl methacrylate cross-linked with divinylazobenzene is able to protect the entrapped drug against the digestive enzymes of the stomach and upper portion of the small intestine, and that the polymer is degraded upon arrival at the colon. Indeed, when incubated in fecal content of rat or human for eight days, perforation of the polymer coat was detected microscopically. In addition, sustained pharmacological response to the encapsulated drug was observed when the coated delivery systems were orally administered to rats, and later to dogs. [M. Saffran, et al., Diabetes 38S: 81A (1989)]
A colonic delivery system for delivering a drug to the colon is disclosed in U.S. Pat. No. 5,525,634 and U.S. Pat. No. 5,866,619. The system comprises a drug in combination with a saccharide-containing polymer matrix. According to the invention, the matrix is resistant to chemical and enzymatic degradation in the stomach and small intestine. The matrix is degraded in the colon by bacterial enzymatic action, and the drug is released. The system is useful for targeting drugs to the colon in order to treat colonic disease. The system is also useful for enteric administration of drugs that are otherwise absorbed or degraded in the stomach and small intestine.
All of these investigational approaches, however, provide for drug delivery only to the colon. Delivery of therapeutic doses of ASA to the ileum or to the ileum and colon is not achieved.
There exists a need, therefore, for improved ASA prodrugs that can be used to deliver therapeutically effective doses of ASA topically to the ileum and to the ileum and colon following oral administration in pharmaceutical compositions.